Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

EEF1A2 : complex neurodevelopmental disorder

HGNC:3192 | MONDO_0100038
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Epilepsy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 15
de Ligt J et al. 2012 Nov 15 (PMID:23033978); Veeramah KR et al. 2013 Jul (PMID:23647072); Nakajima J et al. 2015 Apr (PMID:24697219); Inui T et al. 2016 May (PMID:26682508); Lopes F et al. 2016 Mar (PMID:26740508); Lam WW et al. 2016 Jul (PMID:27441201); de Kovel CG et al. 2016 Sep (PMID:27652284);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
de Kovel CG et al. 2016 Sep (PMID:27652284); Fagerberg L et al. 2014 Feb (PMID:24309898);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Dickinson ME et al. 2016 Sep 22 (PMID:27626380);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 2 14 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
EEF1A2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (de Ligt et al., 2012; PMID: 23033978). At least 17 unique variants (missense) have been reported in at least 28 humans (reviewed in Cao et al., 2017 PMID: 28911200; and Lam et al., 2016 PMID: 27441201).Most of these cases are asserted to have occurred de novo. A website dedicated to EEF1A2 and epilepsy maintained by the Cathy Abbot Lab (IGMM, University of Edinburgh) outlines variants of interest, patients numbers, and references ( Evidence supporting this gene-disease relationship includes case-level and experimental data. More evidence is available in the literature, however the maximum score for genetic evidence (12 points) has been reached. The mechanism for the disease is presumed loss of protein function (Cao et al., 2017 PMID: 28911200). EEF1A2 has been associated with the following disease entities in the literature or nosological or ontological sites: (1) Epileptic encephalopathy, early infantile, 33 (EIEE33; MIM: 616409); (2) Mental retardation, autosomal dominant 38 (MR38; MIM: 616393); (3) Cardiac, intellectual disability, epilepsy syndrome autosomal recessive inheritance (Cao et al., 2017 PMID: 28911200). Per the criteria outlined by the ClinGen Lumping and Splitting Working Group we found no difference in the molecular mechanism, phenotypic expressivity, or inheritance pattern between the Epileptic encephalopathy, early infantile, 33 (MIM: 616409) and Mental retardation, autosomal dominant 38 (MIM: 616393) and have lumped these disease entities into the broader entity of complex neurodevelopmental disorder. However, per the lumping and splitting criteria we found differences in the phenotypic expressivity and inheritance pattern in for cardiac, intellectual disability, epilepsy syndrome (Cao et al., 2017 PMID: 28911200) compared to the EIEE33 and MR38, therefore this gene-disease relationship represents a separate, independent curation and is not currently represented in this gene-disease classification. In summary, EEF1A2 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on March 19, 2019 (SOP version 6).